The human eye is an extremely powerful focusing device that produces an image on the surface of the retina. The focusing elements of the eye are the cornea and the lens. The cornea accounts for approximately 80 percent of the focusing ability (48 diopters) and the lens approximately 20 percent (12 diopters). In the case of myopia, the eye is assumed to have a longer egg-like shape in which case the light beam focuses to a spot located in front of the retina and therefore is out of focus. In hyperopia, the focusing system is inadequate, and the focusing spot and image are located behind the retina and also out of focus. In the case of astigmatism, a spot or clear image is not created, and the eye basically focuses at two areas behind or in front of the retinal surface. In order to correct myopia, hyperopia, or astigmatism, spectacles or contact lenses are used to place the image directly on the rods and cones of the retina.
The cornea is a thin shell with nearly concentric anterior and posterior surfaces and a central thickness of about 520 micrometers. It has an index of refraction of 1.377 and a nominal radius of curvature of 7.86 mm. The epithelium, forming the anterior surface of the cornea, is about 50 micrometers thick. The epithelial cells are capable of very rapid regrowth, and it is known that the epithelium can be removed from the cornea and will quickly regrow to resurface the area from which it was removed. Underlying the epithelium is a layer called Bowman's layer or Bowman's membrane, which is about 20 micrometers thick. This covers the anterior surface of the stroma, which makes up the bulk of the cornea and consists primarily of collagen fibers. The endothelium, forming the posterior layer of the cornea, is a single layer of cells that do not reproduce.
Damage to the corneal epithelium, such as by abrasion or other trauma, is quickly repaired (usually within 24-48 hours) by growth of the rapidly dividing epithelial cells. However, this rapid proliferation of corneal epithelial cells can frequently lead to the development of scar tissue. The presence of scar tissue in the cornea results in `corneal haze`--an opacification of the cornea in which vision is dramatically reduced due to the inability of light to pass through the cornea. Treatment of corneal opacification varies with the extent of scar tissue formation. In cases where the scarring remains light and affects only the surface of the cornea, surgery or laser removal is the treatment of choice. In situations where the scar tissue extends deeper into the cornea removal of the entire tissue and transplantation of a new cornea is the recommended treatment. Prevention of scarring in this tissue after injury is thus a critical step in the preservation of vision.
A number of corneal injuries are known to typically produce scarring of the cornea. These fall into three broad categories: trauma, infection, and disease conditions. Natural traumas (such as abrasion or chemical burns), as well as trauma associated with medical correction of vision (such as photoablation, or contact lens-induced injury) cause disruption of the normal corneal epithelium, resulting in rapid growth of these cells and formation of scar tissue. Damage to the cornea resulting from surgery, such as transplantation, also commonly leads to scarring of this tissue.
Infections of the eye by bacteria, viruses, or fungi can also lead to scarring. For example, ocular infection by herpes simplex virus type I, Pneumococcus, Staphylococcus, Escherichia coli, Proteus, Klebsiella and Pseudomonas strains are known to cause ulcer formation on the surface of the cornea. Such ulcers not only destroy the surrounding epithelial layer, but also penetrate and damage the corneal stroma, further aided by acute inflammatory cells and collagenase released by the injured epithelial cells themselves. Such deep and extensive damage to the cornea and surrounding tissues results in extensive scarring. Other, non-ulcerative pathogens are also known to lead to scarring of the cornea. One such organism is herpes zoster virus (shingles); infection by this organism causes abrasions to the corneal epithelium which frequently result in scarring.
A number of disease conditions not immediately caused by a pathogen or trauma have also been implicated in corneal opacification due to scarring. Two such conditions are cicatricial pemphigoid and Stevens-Johnson syndrome (SJS). Cicatricial pemphigoid is an autoimmune blistering disease affecting oral mucosa and the conjunctiva of the eye, in which inflammation of the corneal epithelium leads to scarring. SJS is a severe form of erythema multiforme, an immune complex-mediated hypersensitivity reaction. The ocular manifestation of this disease is ulceration of the epithelium, followed by severe scarring.
While treatments exist for each of the specific injuries enumerated above, there does not exist in the art a reliable method for reducing or eliminating scarring after corneal injury such that corneal opacification is prevented. The study of corrective vision treatments by photoablation has provided a model system for examining the scarring response and treatments devoted thereto in corneal tissue.
Laser photoablation of corneal tissue can be utilized to correct refractive errors in the eye. About three-quarters of the refractive power of the eye is determined by the curvature of the anterior surface of the cornea, so that changing the shape of the cornea offers a way to significantly reduce or eliminate a refractive error of the eye. Since the epithelium readily regrows, a change in the shape of the anterior surface of the cornea must be made by modifying Bowman's layer and the stroma to be permanent. The stroma is thick enough so that portions of its anterior region can be ablated away to change its profile and thus change the refractive power of the eye for corrective purposes, while leaving plenty of remaining stroma tissue. For example, a change of 5 diopters requires only 27 microns of stromal removal within a 4 mm diameter region.
As discovered by Stephen L. Trokel ("Excimer laser Surgery of the Cornea", American Journal of Ophthalmology, December 1983), far ultraviolet radiation from an excimer laser can be used to change the refractive power of the cornea of an eye. The radiation ablates away corneal tissue in a photodecomposition that does not cause thermal damage to adjacent tissue and can be called photorefractive keratectomy (PRK). A similar photodecomposition of corneal tissue can be achieved with an infrared laser operating near 2.9 micrometers, where thermal damage to adjacent tissue is minimized by the high absorption of water.
L'Esperance U.S. Pat. No. 4,665,913 describes procedures for changing the contour of the anterior surface of the cornea of the eye by directing pulses from an excimer laser in a scanning pattern that moves around the cornea. The laser pulses first ablate and remove the epithelium of the cornea, and then the ablation penetrates into the stroma of the cornea to change its contour for various purposes, such as correcting myopia or hyperopia. Schneider et al. U.S. Pat. No. 4,648,400 suggests radial keratectomy with an excimer laser that also ablates away the epithelium before penetrating into and changing the contour of, the stroma of the cornea.
Ultraviolet laser based systems and methods which are known for enabling ophthalmological surgery on the surface of the cornea in order to correct vision defects by the technique known as ablative photodecomposition. In such systems and methods, the irradiated flux density and exposure time of the cornea to the ultraviolet laser radiation are so controlled as to provide a surface sculpting of the cornea to achieve a desired ultimate surface change in the cornea, all in order to correct an optical defect. Such systems and methods are disclosed in the following U.S. patents and patent applications, the disclosures of which are hereby incorporated by reference. U.S. Pat. No. 4,665,913 issued May 19, 1987 for "METHOD FOR OPTHALMOLOGICAL SURGERY"; U.S. Pat. No. 4,669,466 issued Jan. 2, 1987 for "METHOD AND APPARATUS FOR ANALYSIS AND CORRECTION OF ABNORMAL REFRACTIVE ERRORS OF THE EYE"; U.S. Pat. No. 4,732,148 issued Mar. 22, 1988 for "METHOD FOR PERFORMING OPHTHALMIC LASER SURGERY"; U.S. Pat. No. 4,770,172 issued Sep. 13, 1988 for "METHOD OF LASER-SCULPTURE OF THE OPTICALLY USED PORTION OF THE CORNEA"; U.S. Pat. No. 4,773,414 issued Sep. 27, 1988 for "METHOD OF LASER-SCULPTURE OF THE OPTICALLY USED PORTION OF THE CORNEA"; U.S. patent application Ser. No. 109,812 filed Oct. 16, 1987 for "LASER SURGERY METHOD AND APPARATUS"; and U.S. Pat. No. 5,163,9034 issued Nov. 17, 1992 for "PHOTOREFRACTIVE KERATECTOMY".
In the above-cited U.S. Pat. No. 4,665,913 several different techniques are described which are designed to effect corrections for specific types of optical errors in the eye. For example, a myopic condition is corrected by laser sculpting the anterior corneal surface to reduce the curvature. In addition, a stigmatic condition, which is typically characterized by a cylindrical component of curvature departing from the otherwise generally spherical curvature of the surface of the cornea, is corrected by effecting cylindrical ablation about the axis of cylindrical curvature of the eye. Further, a hyperopic condition is corrected by laser sculpting the corneal surface to increase the curvature.
In a typical laser surgical procedure, the region of the anterior corneal surface to be ablated in order to effect the optical correction is designated the optical zone. Depending on the nature of the desired optical correction, this zone may or may not be centered on the center of the pupil or on the apex of the anterior corneal surface.
A majority of patients develop various degrees of corneal haze following excimer photorefractive keratectomy (PRK) (Lohmann C, Gartry D, Kerr Muir M, et al. "Haze in Photorefractive Keratectomy: Its origins and consequences," Lasers and Light in Ophthal. 1991, 4, 15-34; Fante F E, Hanna K D, Waring G O, et al. "Wound healing after excimer laser keratomileusis (photorefractive keratectomy) in monkeys," Arch.
Ophthal. 1990, 108:665-675). Corneal haze typically peaks at two to four months and has been noted to increase with the degree of myopia corrected (e.g., 2+ stable haze defined according to the standard haze grading scale described by Fante et al., supra., occurs in 11% of patients with corrections greater than eight diopters. Such haze can lead to the loss of one or more lines of best corrected visual acuity after PRK. Corneal stromal remodeling influences the degree of corneal haze after PRK and is believed to be responsible for a reduction in the best possible corrected visual acuity, regression for refractive correction and poor predictability for the attempted correction.
The formation of the corneal haze after PRK is a result of laser corneal ablation and stromal wound healing. Despite significant advances made in understanding PRK technology (e.g., laser-tissue interaction, optical profiling of the laser beam, multi-zone multi-pass approaches and edge-smoothing techniques), characterization of biological aspects associated with PRK, such as wound healing, remains a significant limitation associated with PRK technology (Fante F E, Hanna K D, Waring G O, et cal., "Wound healing after excimer laser keratomileusis (photorefractive keratectomy) in monkeys," Arch. Ophthal. 1990, 108:665-675; Hanna K D, Pouliquen Y, Waring G O, et al., "Corneal stromal wound healing in rabbits after 193-nm excimer laser surface ablation," Arch. Ophthal. 1989, 107:895-901; Holm R J, Fouraker B D, Schanzlin D J. "A comparison of a face and tangential wide-area excimer surface ablation in rabbits," Arch. Ophthal. 1990, 108:876-881; Taylor D M, L'Esperance F A, Del Pera R A, et al., "Human excimer laser lamellar keratectomy, A clinical study," Opthal. 1989, 96:654-664; Marshal J, Trokel S, Rothery S, et al., "Photoablative reprofiling of the corneal using an excimer laser: photorefractive keratectomy," Lasers in Ophthal. 1986,1:21-48; Tuft S, Marshall J, Rothery S. "Stromal remodeling following photorefractive keratectomy," Lasers Ophthal. 1987, 1:177-183). Treatments to reduce corneal haze after PRK have not been proven effective (O'Brat D, Lohmann C P, Klonos G, Corbett M C, Pollock W, Ker-Muir M G and Marshall J., "The effects of topical corticosteroids and plasmin inhibitors on refractive outcome, haze, and visual performance after photorefractive keratectomy," Ophthal. 1994, 101:1565-1574; Gartry, D S, Kerr Muir M G, and Marshall, J, "The effect of topical corticosteroids on refraction and corneal haze following excimer laser treatment of myopia: An update up a Prospective, randomized, double-masked study," Eye 1993, 7:584-590; Bergman R H, Spidelman A V, "The role of fibroblast inhibitors on corneal healing following photorefractive keratectomy with 193-nm excimer laser in rabbits," Ophthal Surg. 1994, 25(3):170-174; Talamo J H, Gollamudi S, Green W R, De La Cruz Z, Filatov V, Stark W J., "Modulation of corneal wound healing after excimer laser keratomileusis using topical mitomycin C and steroids," Arch. Ophthal. 1991, 109(8):1141-1146; Rieck P, David T, Hartman C, Renard G, Courtois Y and Pouliquen Y., "Basic fibroblast growth factor modulates corneal wound healing after excimer laser keratomileusis in rabbits," German J. Ophthal. 1994, 3:105-111; Morlet N, Gillies M C, Grouch R, Mallof A., "Effect of topical interferon-alpha 2b on corneal haze after excimer laser photorefractive keratectomy in rabbits," Refrac. Corneal Surg. 1993, 9(6):443-451; Filipec M, MaiPhan T, Zhao T-Z, Rice B A, Merchant A. and Foster C. Cornea, 1992, 11(6):546-552; Mastubara M, Sasaki A, Ita S., "The effect of active vitamin D to the wound healing after excimer laser phototherapeutic keratectomy (PTK)," ARVO, 1996, 37(3):S198; Nuiizuma T, Ito S, Hayashi M Futemma M, Utsumi T, Ohashi K., "Cooling the cornea to prevent side effects of photorefractive keratectomy," Suppl. to J. Refract. & Corneal Surg. 1994, 10:S262-S266).
These various treatments for reducing corneal haze after excimer laser ablation have met with limited success. For example, the use of topical steroids has been found to be ineffective for the reduction of corneal haze. With regard to refractive outcome, though corticosteroids can maintain a hyperopic shift during their administration. However, the effect is reversed upon cessation of treatment. Consequently, there appears to be no justification for subjecting patients to long-term treatment with steroids for corneal haze in view of adverse side effects associated with steroidal treatments.
Other pharmacological treatments have also not been found to decrease post PRK haze. These treatments have included the use of plasmin inhibitors, fibroblast inhibitors, mitomycin, fibroblast growth factor, interferon-2b, cyclosporin A, active forms of vitamin D, as well as cooling of corneal surface (Rawe I M, Zabel R W, Tuft S J, Chen V and Meek K M., "A morphological study of rabbit corneas after laser keratectomy," Eye 1992, 6:637-642; Wu W C S, Stark W J and Green W R., "Corneal wound healing after 192-nm excimer laser keratectomy,: Arch. Ophthalmol. 1991, 109:1426-1432).